T cells and B cells are thought to play a critical role in the pathogenesis of Multiple Sclerosis. The proposed research proposal will dissect the functions of the ?-secretase and Notch signaling using the experimental autoimmune encephalomyelitis (EAE) models of MS. The goal is to test the suitability of Notch as a therapeutic target in MS. Our preliminary results demonstrate a profound reduction in the severity of EAE when the mice are treated with a small molecule inhibitor of ?-secretase. In order to dissect the role(s) of ?-secretase and Notch signaling we will utilize T cell and B cell-specific Cre recombinase transgenic mice we will generate conditional knockout mice that lack ?-secretase functions by disrupting Presenilin 1 (the catalytic subunit of ?-secretase); and we wil block Notch signaling by blocking Protein-o-fucosyl transferase 1 (POFUT1) a critical glycosyl transferase required for Notch signaling. We will monitor the development of EAE and examine the mice for changes in the underlying T cell differentiation and effector functions as well as the generation of functional MOG-specific B cell responses that are required for this model of EAE. Our overall goal is to determine how ?-secretase or Notch targeted therapies would regulate the immune response and use these experiments as a proof of principle to further pursue these therapies in MS patients.